Registration Dossier

Administrative data

Description of key information

Oral: The oral LD50-values were determined to be 582 mg/kg bw (female, rat) and 681 mg/kg bw (male, rat).
Dermal: No study for sodium cyanate is avaialble. Read across from potassium cyanate was performed instead. It is not expected that Na+ or K+ contribute to dermal toxicity of cyanates. The acute dermal LD50 value of potassium cyanate proved to be greater than 2000 mg/kg bw in male and female Crl:(WI)BR rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-06-14 to 1984-07-13
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
other: References see below
Deviations:
not specified
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
not applicable
Principles of method if other than guideline:
Test is performed according to the following references:
- Bliss, C.J., The Statistics of Bioassay, Academic Press, New York, 1962
- Finney, D.J., Probit Analysis, 2nd Ed. Cambridge Univ. Press, Cambridge 1952
- Hunter, W.J., Link, W. and Recht, P., Intercomparison study on the determination of single administration toxicity in rats, Commission of the European Communities, Health and Safety Directorate, J. Assoc. Off. Anal. Chem. 62, 864 - 873, 1979
- Weber, E., Grundriß d. biol. Statistik, G. Fischer-Verlag, Stuttgart, 7. Auflage, 1972
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- body weight: male 141 - 199 g; female 135 - 163 g
- age: male 57-59 days; female 63 - 72 days
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
not indicated
Doses:
2.15 - 10.0 mL/kg (215 - 1000 mg/kg)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
not indicated
Statistics:
NA
Preliminary study:
NA
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
681 mg/kg bw
Based on:
test mat.
95% CL:
312 - 1 487
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
582 mg/kg bw
Based on:
test mat.
95% CL:
366 - 926
Key result
Sex:
male/female
Dose descriptor:
LD0
Effect level:
215 mg/kg bw
Based on:
test mat.
Mortality:
At the dose of 215 mg/kg, the mortality rate was 0 % and at the dose of 1000 mg/kg, the mortality rate was 80 %.
Clinical signs:
The symptoms of poisoning were disorders of central nervous system and decrease of tonicity . Additional disorders: conical convulsions, tonic convulsions and loss of startle reflexes were showed.
Body weight:
not indicated
Gross pathology:
not indicated
Other findings:
At macroscopic examination of dead animals was showed in female rats of the medium concentration the intestinal mucosa full with a red liquid.

no remarks

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50-values were 582 mg/kg bw (female, rat) and 681 mg/kg bw (male, rat).
Executive summary:

In an acute oral toxicity study, groups of fasted 57-72 days old Wistar rats (3/sex) were given a single oral dose of sodium cyanate (98 %) in water by gavage at doses of 215 to 1000 mg/kg bw.

Oral LD50

Males = 681 mg/kg bw

Females = 582 mg/kg bw

LD0 (male/female) = 215 mg/kg bw

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
582 mg/kg bw
Quality of whole database:
Four different non GLP studies available.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-10-05 to 2009-11-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
30 May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkez u. 90;
- Age at study initiation: 8 weeks;
- Weight at study initiation: males: 244 - 267 g; females. 22 - 233 g;
- Fasting period before study: not stated;
- Housing: during acclimatisation: 3 animals/sex/cage; during the study: animals were housed individually in type-II polypropylene/polycarbonate cages;
- Diet: ssniff SM/ R/m-Z + H complete diet; producer: ssniff Spezialdiäten GmbH, D-59494 Soest, Germany; ad libitum;
- Water: tap water from watering bottles; ad libitum;
- Acclimation period: 9 days;


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):


Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The back of animals was shaven (approximately 10 % area of the total body surface) 24 hours prior to the treatment. The test item was applied in a
single dose uniformly at least 10 % area of the total body surface throughout a 24-hour exposure period. The test item was moistened sufficiently with water to ensure good contact with the skin. Sterile gauze pads were placed on the skin of rats. These gauzes were kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was wrapped with semi-occlusive plastic wrap for 24 hours.
At the end of the exposure period, residual test item was removed, using body temperature water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males; 5 females
Control animals:
no
Details on study design:
The test for acute dermal toxicity was performed in the rats.
In the assessment and evaluation of the toxic characteristic of a substance, determination of acute dermal toxicity is useful where exposure by the
dermal route is likely. It provides information on health hazards likely to arise from a short term exposure by the dermal route. Data from an acute dermal toxicity study may serve as a basis for classification and labelling.
The objective of the study was to reveal, that the dermal LD50 of the test item potassium cyanate is higher than 2000 mg/kg bw after a single 24-hour dermal treatment in rats, therefore a limit test was carried out. No valid in vitro method is available for assessing acute dermal toxicity.


Statistics:
LD50 determination
Preliminary study:
none
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred after the 24-hour dermal exposure to potassium cyanate in Crl:(WI)BR male and female rats during the study.
Clinical signs:
No behavioural changes or general systemic toxic signs were noted during the study. Similarly, no any local symptoms (dermal irritation) were observed on the treated skin of animals as redness and oedema.
Body weight:
The mean body weight and the body weight gain of animals were in the normal range during the two weeks observation period, similar to the
expected values in untreated animals of the same age and strain.
Gross pathology:
No macroscopic alterations due to the effects of the test item were found.
Other findings:
None
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Under the experimental conditions, the acute dermal LD50 value of the test item potassium cyanate proved to be greater than 2000 mg/kg bw in male and female Crl:(WI)BR rats.


Executive summary:

An acute dermal toxicity study was performed with test item potassium cyanate in Crl:(WI)BR rats, in compliance with OECD Guideline No. 402 and Commission Regulation (EC) 440/2008 of 30 May 2008 B.3.

A limit test was carried out. A single group of male and female animals (n=5 animals/sex) was exposed to potassium cyanate at 2000 mg/kg bw by dermal route.

The test item was applied in original form and left in contact with the skin for 24 hours, followed by a 14-day observation period.

No mortality occurred during the study. Neither male nor female animals treated at 2000 mg/kg bw showed behavioural changes and no general toxic signs were noted during the study.

The test item did not cause any dermal irritation symptoms.

The body weight development was undisturbed both in male and female animals.

No macroscopic alterations of organs and tissues referred to the toxic effect of the test item were seen during the necropsy.

 

Under the experimental conditions, the acute dermal LD50 value of the test item potassium cyanate proved to be greater than 2000 mg/kg bw in male and female Crl:(WI)BR rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
One GLP and guideline compliant study available.

Additional information

Oral

Key study:

In an acute oral toxicity study, groups of fasted 57-72 days old Wistar rats (3/sex) were given a single oral dose of sodium cyanate (98 %) in water by gavage at doses of 215 to 1000 mg/kg bw.

Oral LD50

Males = 681 mg/kg bw

Females = 582 mg/kg bw

LD0 (male/fenake) = 215 mg/kg bw

Supporting Studies:

- In an acute oral toxicity study (Report No. 480-83/84), groups of fasted, 57-70 days old Wistar rats (3/sex) were given a single oral dose of sodium cyanate (90 %) in water by gavage at doses of 464, 1000, 2150 mg/kg bw (male) and 215, 464, 1000 mg/kg bw (female) and observed for 14 days.

Oral LD50 = 807 mg/kg bw (571-1140 mg/kg bw).

- In an acute oral toxicity study, groups of Spraque-Dawley rats were given a single oral dose of sodium cyanate in water at increasing doses.

Oral LD50 = 1500 mg/kg bw

Rats that survuved the initial few hours were not permanently affected. Sodium Cyanate is of low Toxicity based on the LD50 in this supporting study.

- In an acute oral toxicity study, groups of mice were given a single oral dose of sodium cyanate.

Oral LDLo = 4 mg/kg bw

This study is of minor quality. No LD50 is given. This study is thus not relevant for determination of the DNEL (acute, oral).

- In human case report a TDLo value of 5400 mg/kg/24W was reported.

Two young patients developed bilateral posterior subcapsular cataracts while receiving oral sodium cyanate for treatment of sickle cell hemoglobinopathy. In one of the patients, lens opacities regressed spontaneously after cyanate therapy was discontinued.

Dermal:

No study for sodium cyanate is avaialble. Read across from potassium cyanate was performed instead. It is not expected that Na+ or K+ contribute to dermal toxicity of cyanates. An acute dermal toxicity study was performed with potassium cyanate in Crl:(WI)BR rats, in compliance with OECD Guideline No.: 402 and Commission Regulation (EC) 440/2008 of 30 May 2008 B.3.

A limit test was carried out. A single group of male and female animals (n=5 animals/sex) was exposed to potassium cyanate at 2000 mg/kg bw by dermal route.

The test item was applied in original form and left in contact with the skin for 24 hours, followed by a 14-day observation period.

No mortality occurred during the study. Neither male nor female animals treated at 2000 mg/kg bw showed behavioural changes and no general toxic signs were noted during the study. The test item did not cause any dermal irritation symptoms. The body weight development was undisturbed both in male and female animals.

No macroscopic alterations of organs and tissues referred to the toxic effect of the test item were seen during the necropsy. Under the experimental conditions, the acute dermal LD50 value of the test item potassium cyanate proved to be greater than 2000 mg/kg bw in male and female Crl:(WI)BR rats. Potassium cyanate does not meet the requirements of EU labelling regulations Commission Regulation (EC) 440/2008of 30 May 2008 B3.

Inhalation:

In accordance with column 2 of REACH Annex VIII, the test acute toxicity after inhalation (required in section 8.5) does not need to be conducted as acute toxicity studies for oral and dermal application are available. Inhalation exposure is regarded negligible as practically no particles below 50 µm were detected in particle size analysis (see IUCLID5 section 4.5) and vapour pressure of sodium cyanate is very low.

Other routes

Supporting studies

- In an acute toxicity study (i.p. administration), groups of B6/D2 F1 mice were given increasing doses of sodium cyanate.

Oral LD50 = 260 mg/kg bw

After the administration of a lethal dose, the mice appeared sedated, but then suddenly developed seizures which could be triggered by noise. Some animals recovered from several of these seizures, but eventually succumbed. The deaths after a letheal dose occured within 15 minutes to one hour after the injection; mice that survived an LD50 dose recovered from the sedation and did not appear permanently affected.

- In an acute toxicity study (unspecified administration), groups of mice were given doses of sodium cyanate.

LD50 = 400 mg/kg bw

Clinical signs:

Behavioral - convulsions or effect on seizure threshold

Behavioral - excitement Lungs, Thorax, or Respiration - dyspnea

- In an acute toxicity study (intramuscular administration), groups of mice were given doses of sodium cyanate.

LD50 = 310 mg/kg bw

Clinical signs:

Behavioral - altered sleep time (including change in righting reflex)

Behavioral - convulsions or effect on seizure threshold

Kidney/Ureter/Bladder - urine volume increased

- In an acute toxicity study (unspecified administration), groups of rats were given doses of sodium cyanate.

LD50 = 1000 mg/kg bw

Clinical signs:

Behavioral - convulsions or effect on seizure threshold

Behavioral - excitement Lungs, Thorax, or Respiration - dyspnea

- In an acute neurotoxicity study (see section 7.9.1), groups of 8 male CD-1 mice were given a single dose i.p. of sodium in water and observed for 24 hours.Neurobehavioral assessment (functional observation battery and motor activity testing) was performed in 5 male animals/group at 45 min after dosing.

The LD50 and median neurotoxic dose (as determined by impairment of rotarod performance) of sodium cyanate (NaOCN) were determined to be 278 and 155 mg/kg bw, ip, respectively. At doses of 38.75-155 mg/kg, NaOCN increased the susceptibility of mice to i.v. pentylenetrazol-induced maximal seizures. The two higher doses of NaOCN decreased the maximal electroshock seizure threshold 21-38 %. The oxygen affinity of haemoglobin was increased 6-10% by NaOCN and P(CO2) values were elevated. The results of this study suggest that hypoxia may play a contributory role in cyanate-induced and potentiated seizure susceptibility in mice.



Justification for selection of acute toxicity – oral endpoint
The most reliable study was selected.

Justification for selection of acute toxicity – dermal endpoint
GLP and guideline compliant study.

Justification for classification or non-classification

Based on the results obtained in the acute oral toxicity studies (LD50(female, rat) = 582 mg/kg bw) and taking into account the provisions laid down in Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776, sodium cyanate has to be classified in acute toxicity category 4 (H302: Harmful if swalloed).

 

Based on the results obtained in the acute dermal toxicity study (oral: LD50(rat) > 2000 mg/kg bw) and taking into account the provisions laid down in Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776, sodium cyanate has not to be classified regarding acute dermal toxicity.